7-(1,3-Dithiolan-2-imino)cephalosporanic acid derivatives

ABSTRACT

Novel 7-(1,3-dithiolan-2-imino)cephalosporin derivatives are described which are particularly useful for their antibacterial properties.

This is a division of application Ser. No. 19,417, filed Mar. 12, 1979,now U.S. Pat. No. 4,206,305.

DESCRIPTION

1. Technical Field

This invention relates to certain cephalosporin derivatives useful asantibacterial agents and to a method for their preparation.

2. Background Art

Compounds with a cephalosporin nucleus belong to a well-known family ofantibiotics that have been widely used in recent years for the treatmentof various infectious diseases. A number of commercially usefulcephalosporin antibiotics have been obtained by varying the substitutionat the 3-position of the cephalosporin nucleus and by variousmodifications of the side-chain substitutents at the 7-position of thecephalosporin nucleus. The search continues, however, for new compoundswhich possess a broad spectrum of antibacterial activity and whichpossess a high degree of activity toward both gram-positive andgram-negative bacteria without causing undesirable contraindicationswhen administered to humans.

In an effort to improve the properties of existing compounds, effortshave been directed towards the insertion of a 1,3-dithiolane ringdirectly onto the 7-position of the cephalosporin nucleus to producecompounds that are useful antibacterial agents. More particularly thepreparation of cephalosporanic acid derivatives having a1,3-dithiolan-2-imino moiety located at the 7-position of thecephalosporin nucleus provides novel cephalosporin derivatives that areeffective against one or more gram-positive and gram-negativemicroorganisms. Accordingly, the compounds of the present invention areeffective in the treatment of various infectious diseases caused by suchgram-positive and gram-negative bacteria in poultry or in mammals,including man. The compounds disclosed herein are also suitable for usein certain topical germicidal preparations or as surface disinfectants.

SUMMARY OF THE INVENTION

In accordance with the present invention certain novel7-(1,3-dithiolan-2-imino) derivatives of cephalosporanic acid aredescribed, which are useful for their antibacterial properties. Moreparticularly, the present invention relates to7-(1,3-dithiolan-2-imino)cephalosporanic acid derivatives having theformula ##STR1## wherein R₁ is selected from the group consisting ofhydrogen, hydroxy, acetoxy, 5-methyl-1,3,4-thiadiazol-2-ylthio,1-methyl-1,2,3,4-tetrazol-5-ylthio and 1,2,3-triazol-4-ylthio; R₂ isselected from the group consisting of hydrogen, t-butyl,2,2,2-trichloroethyl, benzhydryl, formyloxymethyl and alkanoyloxymethylin which the alkanoyl group contains from 2 to 5 carbon atoms; and thepharmaceutically acceptable salts thereof.

Another aspect of the present invention relates to the preparation ofthese novel 7-(1,3-dithiolan-2-imino) cephalosporanic acid derivativesby condensing in solution an S-alkylated salt of 1,3-dithiolane-2-thionewith a 7-aminocephalosporanic acid having the formula ##STR2## whereinthe symbols R₁ and R₂ are as previously defined. This process is ofparticular advantage in that it provides, for the first time, aconvenient method enabling the direct insertion of a1,3-dithiolan-2-imino moiety at the 7-position of the cephalosporanicnucleus in good yield.

DETAILED DESCRIPTION OF THE INVENTION

As can be seen in formula (I) above, all of the derivatives of thepresent invention contain a 1,3-dithiolan-2-imino moiety attached to the7-position of the cephalosporin nucleus. The term cephalosporanic acidderivatives as used herein relates generically to the specificcephalosporanic acids defined by the various substituents on the3-methyl group of the cephalosporin nucleus. Thus, where the symbol R₁is hydrogen, the compounds are designated as desacetoxycephalosporanicacids. When R₁ represents the hydroxyl group, the compounds aredesignated as belonging to the class of desacetylcephalosporanic acids.When the symbol R₁ represents the acetoxy group, the compounds arespecifically designated as belonging to the class of cephalosporanicacids. Finally, the symbol R₁ can represent a heterocyclic thioetherattached to the 3-methyl group of the cephalosporin nucleus. Thepreferred heterocyclic thioethers described herein include the5-methyl-1,3,4-thiadiazol-2-ylthio group, the1-methyl-1,2,3,4-tetrazol-5-ylthio group and the 1,2,3-triazol-4-ylthiogroup. In order to be consistent with the nomenclature employed, theseheterocyclic thioethers are designated as3-[(heterocycle-ylthio)methyl]decephalosporanic acids.

The compounds contemplated within the scope of this invention includenot only the free cephalosporanic acids, but certain esters thereof asfurther indicated by the symbol R₂. Thus, where the symbol R₂ representshydrogen, the free acid is designated. The preferred cephalosporanicacid ester groups include the t-butyl, 2,2,2-trichloroethyl, benzhydryl,formyloxymethyl and alkanoyloxymethyl groups. The term alkanoyl as usedin this regard includes those groups having a total of from 2 to 5carbon atoms, as for example, the acetyl, propionyl, butyryl,isobutyryl, 2-methylbutyryl, 3-methylbutyryl and 2,2-dimethylpropionylgroups. In general, these ester groups confer improved absorptionproperties upon the molecule, while remaining physiologically labile.Such esters are readily absorbed from the gastrointestinal tract,thereby promoting oral activity, whereupon they are enzymaticallyhydrolyzed to the corresponding free, and generally more active,cephalosporanic acids. Such esters are readily prepared in accordancewith the procedures described by Binderup et al., Journal ofAntibiotics, 24, 767 (1971).

The pharmaceutically acceptable salts of the compounds of formula (I)include the non-toxic, carboxylic acid salts that are formed with anysuitable inorganic or organic base. Illustratively, these salts includethose of alkali metals, as for example, sodium and potassium; alkalineearth metals, such as barium, calcium and magnesium; light metals ofGroup III A including aluminum; and organic primary, secondary andtertiary amines including triethylamine, procaine, dibenzylamine,vinylamine, N,N'-dibenzylethylenediamine, dihydroabietylamine,N-(lower)alkylpiperidine and various other amines that have been used toform non-toxic salts of antibiotics such as benzylpenicillin. Thesesalts are prepared via conventional methods known to those skilled inthe art, as for example by the neutralization of a solution of the freecarboxylic acid in a polar solvent using a stoichiometric quantity ofbase, and recovering the salt therefrom.

Illustrative compounds encompassed by formula (I) above include:

7-(1,3-dithiolan-2-imino)cephalosporanic acid,

t-butyl 7-(1,3-dithiolan-2-imino)cephalosporanate,

2,2,2-trichloroethyl 7-(1,3-dithiolan-2-imino)cephalosporanate,

benzhydryl 7-(1,3-dithiolan-2-imino)cephalosporanate,

formyloxymethyl 7-(1,3-dithiolan-2-imino)cephalosporanate,

pivaloyloxymethyl 7-(1,3-dithiolan-2-imino)cephalosporanate,

7-(1,3-dithiolan-2-imino)desacetylcephalosporanic acid,

t-butyl 7-(1,3-dithiolan-2-imino)desacetylcephalosporanate,

benzhydryl 7-(1,3-dithiolan-2-imino)desacetylcephalosporanate,

acetyloxymethyl 7-(1,3-dithiolan-2-imino)desacetylcephalosporanate,

butyryloxymethyl 7-(1,3-dithiolan-2-imino)desacetylcephalosporanate,

7-(1,3-dithiolan-2-imino)desacetoxycephalosporanic acid,

t-butyl 7-(1,3-dithiolan-2-imino)desacetoxycephalosporanate,

2,2,2-trichloroethyl7-(1,3-dithiolan-2-imino)desacetoxycephalosporanate,

formyloxymethyl 7-(1,3-dithiolan-2-imino)desacetoxycephalosporanate,

pivaloyloxymethyl 7-(1,3-dithiolan-2-imino)desacetoxycephalosporanate,

7-(1,3-dithiolan-2-imino)-3-[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanicacid,

t-butyl7-(1,3-dithiolan-2-imino)-3-[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanate,

benzhydryl 7-(1,3-dithiolan-2-imino)-3-[(5-methyl1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanate,

acetyloxymethyl7-(1,3-dithiolan-2-imino)-3-[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanate,

2-methylbutyryloxymethyl7-(1,3-dithiolan-2-imino)-3-[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanate,

7-(1,3-dithiolan-2-imino)-3-[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalosporanicacid,

t-butyl7-(1,3-dithiolan-2-imino)-3-[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalosporanate.

2,2,2-trichloroethyl7-(1,3-dithiolan-2-imino)-3-[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalosporanate,

formyloxymethyl7-(1,3-dithiolan-2-imino)-3-[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalosporanate,

pivaloyloxymethyl7-(1,3-dithiolan-2-imino)-3-[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalosporanate,

7-(1,3-dithiolan-2-imino)-3-[(1,2,3-triazol-4-ylthio)methyl]decephalosporanicacid,

t-butyl7-(1,3-dithiolan-2-imino)-3-[(1,2,3-triazol-4-ylthio)methyl]decephalosporanate,

benzhydryl7-(1,3-dithiolan-2-imino)-3-[(1,2,3-triazol-4-ylthio)methyl]decephalosporanate,

acetyloxymethyl7-(1,3-dithiolan-2-imino)-3-[(1,2,3-triazol-4-ylthio)methyl]decephalosporanate,and

3-methylbutyryloxymethyl7-(1,3-dithiolan-2-imino)-3-[(1,2,3-triazol-4-ylthio)methyl]decephalosporanate.

The compounds represented by claim 1 are readily prepared in good yieldby condensing an S-alkylated salt of 1,3-dithiolane-2-thione (III) witha 7-aminocephalosporanic acid. This reaction sequence is indicated asfollows wherein the symbols R₁ and R₂ are as previously defined and thesymbol X represents a halogen atom selected from the group consisting ofchlorine, bromine and iodine. ##STR3##

The S-alkylated salts of 1,3-dithiolane-2-thione are readily prepared bythe alkylation of 1,3-dithiolane-2-thione, which is known commerciallyas ethylenetrithiocarbonate. Thus, for example, the addition of a methylhalide with stirring to a solution of 1,3-dithiolane-2-thione at atemperature ranging from 0° to about 50° C. for a period of from 1 to 24hours results in the formation of the corresponding S-methyl halide saltof 1,3-dithiolane-2-thione as a crystalline salt. This S-methyl iodidesalt of 1,3-dithiolane-2-thione is the alkylated salt of choice and isprepared by the addition of methyl iodide to a solution of1,3-dithiolane-2-thione. Preferably, the reaction is conducted via thedropwise addition of methyl iodide to a nitromethane solution of1,3-dithiolane-2-thione at room temperature under an inert atmospheresuch as nitrogen or argon.

The various 7-aminocephalosporanic acids employed herein (II) arewell-known compounds previously described in the literature. Thus,hydrolysis of cephalosporin C results in the formation of7-aminocephalosporanic acid as described by Loder et al., Biochem. J.79, 408-16 (1961) and represented by the formula ##STR4##

The compound 7-aminodesacetoxycephalosporanic acid, having the formula##STR5## is prepared by the catalytic reduction of cephalosporin C,followed by the hydrolytic removal of the 5-aminoadipoyl side chain asdescribed in U.S. Pat. No. 3,129,224.

Treatment of cephalosporin C with an acetyl esterase prepared fromorange peel as described by Jeffery et al., Biochem J. 81, 591 (1961)results in the formation of 3-hydroxymethyl-7-aminodecephalosporanicacid, as designated herein, or 7-aminodesacetylcephalosporanic acid,which has the formula ##STR6##

The 7-aminocephalosporanic acid derivatives (II) are readily condensedas their free acids to form the 7-(1,3-dithiolan-2-imino)cephalosporanic acid derivatives (I) of the present invention.Preferably, however, they are condensed in the form of their salts ortheir esters. Suitable salts include the sodium and trialkylamine salts,in which the alkyl group contains from 1 to 5 carbon atoms. Suitableesters include any of the esters disclosed in U.S. Pat. No. 3,284,451,or any of the silyl esters analogously disclosed in U.S. Pat. No.3,249,622. The condensed esters are readily isolated to yield theproducts of the present invention or, as in the case of the silylesters, they are readily cleaved to yield the free acids of the various7-(1,3-dithiolan-2-imino) cephalosporanic acid derivatives.

In general, the condensation of the 7-aminocephalosporanic acidderivatives (II) and the S-alkylated salts of 1,3-dithiolan-2-thione(III) is conducted in the presence of a suitable solvent at temperaturesranging from -30° C. to 100° C. The reaction time varies from 15 minutesto as long as 36 hours depending upon the particular reactiontemperature employed. For convenience, the reaction is preferablyconducted at room temperature or slightly below for a period of from 1to 8 hours.

Suitable solvents in which the condensation takes place include acetone,acetonitrile, dioxane, dimethylformamide, chloroform, ethylene chloride,dichloromethane and tetrahydrofuran with acetonitrile being theparticular solvent of choice. In certain instances, as when the7-aminocephalosporanic acid starting materials are present in the formof a salt, mixtures of water and a miscible organic solvent may beadvantageously employed. Optionally, the condensation can be conductedin the presence of an inert atmosphere, as for example argon or nitrogengas. An excess of the S-alkylated salt of 1,3-dithiolane-2-thione (III)is also favorably employed to insure completeness of the reaction and tofavor the yield of desired product obtained.

Following completion of the condensation reaction, the reaction mixtureis generally quenched in water and the desired7-(1,3-dithiolan-2-imino)cephalosporanic acid derivatives isolated viastandard procedures known to those versed in the art. Thus, for example,the quenched reaction mixture is extracted with a suitable organicsolvent, such as chloroform, methylene chloride or ether, the organicextract is washed with a dilute aqueous acid solution to remove anyunreacted starting material, the washed organic extract is dried,concentrated and the desired 7-(1,3-dithiolan-2-imino)cephalosporanicacid derivatives recovered therefrom. Purification of the products isgenerally effected by recrystallization from suitable organic solventssuch as chloroform or from a chloroform-ether mixture.

Where the 7-aminocephalosporanic acid derivatives used as startingmaterials (II) are present as the free acid, i.e., where the symbol R₂is hydrogen, the use of a silylating agent is advantageously employed.Under these circumstances the condensation best proceeds under anhydrousconditions in anhydrous solvents in which the free acids are not toosoluble. The silylating agents employed form labile silyl esters withthe various 7-aminocephalosporanic acid and are readily soluble inanhydrous solvents. Inasmuch as these silyl esters are highly sensitiveto moisture, once condensation has taken place, the esters are readilyhydrolyzed to the free acid by quenching the reaction mixture in water.Suitable silylating agents that may be favorably employed includevarious alkyl chlorosilanes, alkyl disilazanes, alkyl silylamines andalkylsilylamides, as for example triethyl chlorosilane, tri-n-butylchlorosilazane, dimethylethyl chlorosilane, phenylethylmethylchlorosilane, triphenyl chlorosilane, tetraethyldimethyl disilazane,hexamethyl disilazane, tetramethyldiphenyl disilazane, hexaphenyldisilazane, N-ethyl triethyl silylamine, triphenyl silylamine,N-trimethylsilylacetamide with the silylating agent of choice beingO,N-bis-trimethylsilylacetamide.

In general, the free acids of the 7-aminocephalosporanic acidderivatives (II), are suspended in a suitable anhydrous solvent, as forexample acetonitrile, tetrahydrofuran or dioxane. Two equivalents of thesilylating agent are added to this suspension and stirring is continueduntil esterification and solution occur, generally in about two hours orless at room temperature. An additional 10% excess of the silylatingagent is added to insure complete esterification of the particular7-aminocephalosporanic acid employed. Condensation with an S-alkylatedsalt of 1,3-dithiolane-2-thione and the subsequent isolation of thedesired products remain essentially as previously described.

A preferred group of 7-(1,3-dithiolan-2-imino) cephalosporanic acidderivatives are those containing a methylthioheterocycle group at the3-position of the cephalosporin nucleus. In addition to the condensationprocedure described above, these compounds can be prepared by thedisplacement of the 3-acetoxy group of a salt or ester of7-(1,3-dithiolan-2-imino)cephalosporanic acid. This displacement orsolvolysis of the acetoxy group at the 3-methyl position of thecephalosporin nucleus is a well-known reaction described in U.S. Pat.Nos. 3,516,997 and 3,641,021. The acetoxy group is readily displacedwith a heterocyclic thiol, such as 5-methyl-1,3,4-thiadiazol-2-ylthio,1-methyl-1,2,3,4-tetrazol-5-thiol or 1,2,3-triazol-4-thiol attemperatures ranging from about 25° C. to 150° C. in aqueous solventssuch as water or buffered aqueous solutions. Preferably, a temperaturerange of from 50° C. to 100° C. is employed in combination with abuffered aqueous solution having a pH ranging from 4.0 to 9.0. Suitableaqueous solutions include those selected from the group consisting ofwater, or an aqueous solution of acetone, tetrahydrofuran anddimethylformamide.

In certain instances the displacement of the acetoxy group from themethyl group at the 3-position results in the migration of the doublebond to the 3-position of the β-lactam nucleus. Under thosecircumstances the position of the double bond can be re-established bythe oxidation of the ring sulfur to the sulfoxide with such oxidizingagents as hydrogen peroxide, sodium metaperiodate or an organic peracid.Subsequent reduction of the sulfoxide by means of catalytichydrogenation or sodium dithionite provides the desired cephalosporinderivatives which are unsaturated in the Δ² -position of thecephalosporin nucleus.

The novel compounds of the present invention are useful antimicrobialagents having a broad spectrum of antimicrobial activity in vitroagainst standard laboratory microorganisms that are routinely used todemonstrate activity against pathogenic bacteria. The antibacterialspectrum of typical compounds described herein is determined in astandard manner by means of a qualitative diffusion assay as illustratedin Example 7 below. The in vitro antibacterial activity of the novelcompounds of this invention not only makes them useful aspharmacological agents per se, but makes them useful as additives foranimal feeds, as well as additives for materials which are subject tomicrobial deterioration, such as cutting oils and fuel oils. Thesecompounds are also useful for their antibacterial effect in soaps,shampoos and in topical compositions for the treatment of wounds andburns.

The invention described herein is more particularly illustrated inconjunction with the following specific examples.

EXAMPLE 1 S-Methyl 1,3-dithiolane-2-thione iodide

1,3-Dithiolane-2-thione, (ethylenetrithiocarbonate) 13.6 g, is dissolvedin 25 ml of reagent nitromethane and treated at room temperature with14.2 g of methyl iodide via dropwise addition with stirring under anatmosphere of nitrogen. The reaction mixture is wrapped with foil forlight protection and stirring is continued overnight. The crystals thatform are filtered, washed with dry benzene and dried in vacuo to yield20.9 g of brown colored, crystalline S-methyl 1,3-dithiolane-2-thioneiodide having a m.pt. of 80°-3° C.

EXAMPLE 2 t-Butyl 7-(1,3-dithiolan-2-imino)desacetoxycephalosporanate

t-Butyl 7-aminodesacetoxycephalosporanate, 2.7 g, is dissolved in 50 mlof dry acetonitrile, and 6.02 g of S-methyl 1,3-dithiolane-2-thioneiodide, prepared in accordance with the preceding Example, is added withstirring thereto. Stirring is continued at room temperature forapproximately 16 hours. The reaction mixture is filtered, quenched inwater and the aqueous mixture extracted with chloroform. The chloroformextracts are combined, washed with a dilute 0.1 N solution ofhydrochloric acid, dried over anhydrous MgSO₄, filtered and concentratedto dryness in vacuo. The residue is recrystallized from a hot chloroformsolution to yield approximately 1.62 g of off-white colored t-butyl7-(1,3-dithiolan-2-imino)desacetoxycephalosporanate having a m.pt. of180°-181° C.

Following essentially the same procedure and substituting2,2,2-trichloroethyl 7-aminocephalosporanate, formyloxymethyl7-amino-3-[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanateand pivaloyloxymethyl7-amino-3-[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalosporanatefor the t-butyl 7-aminodesacetoxycephalosporanate above results in theformation of 2,2,2-trichloroethyl7-(1,3-dithiolan-2-imino)cephalosporanate, formyloxymethyl7-(1,3-dithiolan-2-imino)-3-[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanateand pivaloyloxymethyl7-(1,3-dithiolan-2-imino)-3-[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalosporanate,respectively.

EXAMPLE 3 7-(1,3-Dithiolan-2-imino)desacetoxycephalosporanic acid

The compound 7-aminodesacetoxycephalosporanic acid, 4.55 g, is suspendedwith stirring in 120 ml of dry acetonitrile under a blanket of argon gasand 5.8 ml of bis-trimethylsilylacetamide added thereto. Stirring iscontinued for approximately 2 hours until solution occurs and 6.95 g ofS-methyl 1,3-dithiolan-2-thione iodide is added together with anadditional 30 ml of dry acetonitrile. The reaction mixture is stirred atroom temperature for an additional hour quenched in 250 ml of water, andextracted with chloroform. The combined chloroform extracts are washedonce with a saturated NaCl solution, dried over anhydrous MgSO₄,filtered and evaporated to dryness in vacuo. The residue is trituratedwith ether and is crystallized from an acetoneether solution to yield2.80 g of an off-white crystalline material having a m.pt. of 176°-7° C.(dec.), whose infrared and nuclear magnetic resonance spectra areconsistent with that of the desired7-(1,3-dithiolan-2-imino)desacetoxycephalosporanic acid.

Following essentially the same procedure, but substituting7-aminodesacetylcephalosporanic acid, and7-amino-3-[(1,2,3-triazol-4-ylthio)methyl]decephalosporanic acid for the7-aminodesacetoxycephalosporanic acid above results in the formation of7-(1,3-dithiolan-2-imino)desacetylcephalosporanic acid, and7-(1,3-dithiolan-2-imino)-3-[(1,2,3-triazol-4-ylthio)methyl]decephalosporanicacid, respectively.

EXAMPLE 4 7-(1,3-Dithiolan-2-imino)cephalosporanic acid

The compound 7-aminocephalosporanic acid, 0.27 g, is suspended in 20 mlof dry acetonitrile, treated with 0.23 ml of bis-trimethylsilylacetamideunder a blanket of argon gas and stirred for approximately 2 hours atroom temperature until solution occurs. The compound S-methyl1,3-dithiolane-2-thione iodide, 0.30 g, is added to the silyl estersolution and stirring is continued overnight at room temperature. Thereaction mixture is quenched in water and the aqueous mixture isextracted with chloroform. The combined chloroform extracts are washedwith a saturated solution of sodium chloride, dried over anhydrousMgSO₄, filtered and evaporated to dryness in vacuo to yield ayellowish-brown residue. Crystallization of this material fromacetone-methanolether affords 0.193 g of 7-(1,3-dithiolan-2-imino)cephalosporanic acid having a m.pt. of 167°-9° C. (dec).

Following essentially the same procedure but subsituting7-amino-3-[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanicacid and7-amino-3-[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalosporanicacid for the 7-aminocephalosporanic acid above, results in the formationof7-(1,3-dithiolan-2-imino)-3-[(5-methyl-1,3,4-thiadiazol-2-ylthio)methyl]decephalosporanicacid and7-(1,3-dithiolan-2-imino)-3-[(1-methyl-1,2,3,4-tetrazol-5-ylthio)methyl]decephalosporanicacid, respectively.

EXAMPLE 5 Benzhydryl 7-(1,3-dithiolan-2-imino)desacetoxycephalosporanate

The compound 7-(1,3-dithiolan-2-imino)desacetoxycephalosporanic acidprepared in accordance with the procedure of Example 3, 6.2 g, isdissolved in 250 ml of dry tetrahydrofuran, and treated with 4.0 g ofdiphenyldiazomethane. The purple reaction mixture is stirred at roomtemperature for a period of 24 hours, treated with activated charcoal,filtered and the filtrate evaporated to dryness in vacuo. Trituration ofthe residue so obtained using a 50% acetone/ether solution yieldsapproximately 8.8 g of a yellow powder. Recrystallization of thismaterial using a chloroform-ether solution yields the desired benzhydryl7-(1,3-dithiolan-2-imino) desacetoxycephalosporanate as an off-whitepowder having a m.pt. of 160°-2° C.

Following essentially the same procedure but substituting7-(1,3-dithiolan-2-imino)cephalosporanic acid for the7-(1,3-dithiolan-2-imino)desacetoxycephalosporanic acid above results inthe formation of benzyhydryl 7-(1,3-dithiolan-2-imino)cephalosporanateas an off-white solid having a m.pt. of 200°-2° C.

EXAMPLE 6 7-(1,3-Dithiolan-2-imino)desacetoxycephalosporanic acid

Triethylamine, 5 ml, and 7-aminodesacetoxycephalosporanic acid, 2.14 g.,are dissolved at room temperature in 20 ml of sieve-drieddimethylformamide under an atmosphere of argon gas. To this solution isadded 3.06 g of S-methyl 1,3-dithiolane-2-thione iodide in portions. Thereaction mixture is stirred at room temperature for a period of 2 hoursand quenched into 150 ml of water. The quenched reaction mixture isextracted with four 50 ml portions of methylene dichloride followed byan additional extraction with a 100 ml portion of diethyl ether. Theaqueous solution is adjusted to a pH of 2.5 using a 1 N solution ofhydrochloric acid and extracted with three 100 ml portions ofchloroform. The combined chloroform extracts are washed with a saturatedNaCl solution, dired over anhydrous MgSO₄ and the dried organic extractsare evaporated to dryness in vacuo to yield a solid foam. Trituration ofthis foam with diethyl ether yields7-(1,3-dithiolan-2-imino)desacetoxycephalosporanic acid as previouslydescribed in Example 3.

EXAMPLE 7

The following example illustrates the in vitro activity of the compoundsof this invention.

Trypticase soy broth is inoculated from a slant culture of the testbacterium the day prior to testing. The inoculated broth is incubatedfor 24 hours at 37° C. and 0.05 ml of the inoculated and incubated brothis added to 25 ml of melted (45°-50° C.) trypticase soy agar. The seededagar is poured into a 100 mm square petri dish and allowed to solidify.

Approximately 1 to 3 mg of purified7-(1,3-dithiolan-2-imino)cephalosporanic acid is placed directly uponthe agar and the agar plate incubated overnight. Chloramphenicol issimilarly applied to seeded agar as a reference standard and incubatedovernight. The agar plates are examined for clear zones of bacterialgrowth inhibition. The diameter of each zone is measured and recorded.

The following table summarizes the various zones of inhibition expressedin millimeters observed for the various test organisms.

    ______________________________________                                                       7-(1,3-dithiolan-                                                             2-imino)cephalo-                                                                            chloramphen-                                     Organism       sporanic acid(mm)                                                                           icol(mm)                                         ______________________________________                                        Staphylococcus aureus                                                                        4             29                                               Streptococcus faecalis                                                                       7             39                                               Salmonella schottmuelleri                                                                    4             39                                               Proteus mirabilis                                                                            3             35                                               Pseudomonas aeruginosa                                                                       7             26                                               Escherichia coli                                                                             30            52                                               ______________________________________                                    

Following essentially the same procedure the following zones ofinhibition were observed for the test compound7-(1,3-dithiolan-2-imino)desacetoxycephalosporanic acid.

    ______________________________________                                                       7-(1,3-dithiolan-                                                             2-imino)desacetoxy-                                                           cephalosporanic                                                                             chloramphen-                                     Organism       acid(mm)      icol(mm)                                         ______________________________________                                        Staphylococcus aureus                                                                        6             34                                               Streptococcus faecalis                                                                       4             25                                               Salmonella schottmuelleri                                                                    4             33                                               Proteus mirabilis                                                                            4             25                                               Pseudomonas aeruginosa                                                                       4             18                                               Escherichia coli                                                                             7             39                                               Streptococcus pyogenes                                                                       6             40                                               ______________________________________                                    

What is claimed is:
 1. A 7-(1,3-dithiolan-2-imino)cephalosporanic acidderivative having the formula ##STR7## wherein R₁ is selected from thegroup consisting of 5-methyl-1,3,4-thiadiazol-2-ylthio,1-methyl-1,2,3,4-tetrazol-5-ylthio and 1,2,3-triazol-4-ylthio;R₂ isselected from the group consisting of hydrogen, t-butyl,2,2,2-trichloroethyl, benzhydryl, formyloxymethyl and alkanoyloxymethylin which the alkanoyl group contains from 2 to 5 carbon atoms; andthepharmaceutically acceptable salts thereof.
 2. A compound according toclaim 1 wherein R₂ is hydrogen.
 3. A process for the preparation of a7-(1,3-dithiolan-2-imino)cephalosporanic acid derivative of claim 1which comprises condensing in solution an S-alkylated salt of1,3-dithiolane-2-thione with a 7-aminocephalosporanic acid having theformula ##STR8## wherein the symbols R₁ and R₂ are defined as in claim1, and recovering the cephalosporanic acid derivative therefrom.
 4. Aprocess for the preparation of a7-(1,3-dithiolan-2-imino)cephalosporanic acid derivative of claim 1 inwhich R₂ is hydrogen, which comprises condensing in solution anS-alkylated salt of 1,3-dithiolane-2-thione with a silyl ester of a7-aminocephalosporanic acid having the formula ##STR9## wherein thesymbol R₁ is as defined in claim 1, and recovering the cephalosporanicacid derivative therefrom.